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org/chemneuro Review

Melatonin as an Antiepileptic Molecule: Therapeutic Implications via

Neuroprotective and Inflammatory Mechanisms
Enes Akyuz, Irem Kullu, Alina Arulsamy, and Mohd. Farooq Shaikh*

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ABSTRACT: Epilepsy is a result of unprovoked, uncontrollable, and repetitive outburst

of abnormal and excessive electrical discharges, known as seizures, in the neurons.
Downloaded via UNIV OF CONNECTICUT on May 16, 2021 at 08:03:20 (UTC).

Epilepsy is a devastating neurological condition that affects 70 million people globally.

Unfortunately, only two-thirds of epilepsy patients respond to antiepileptic drugs while
others become drug resistant and may be more prone to epilepsy comorbidities such as
SUDEP. Oxidative stress, mitochondrial dysfunction, imbalance in the excitatory and
inhibitory neurotransmitters, and neuroinflammation are some of the common
pathologies of neurological disorders and epilepsy. Studies suggests that melatonin, a
pineal hormone that governs sleep−wake cycles, may be neuroprotective against
neurological disorders and thus may be translated as an antiepileptic as well. Melatonin
has been shown to be an antioxidant, antiexcitotoxic, and anti-inflammatory hormone/
molecule in neurodegenerative diseases, which may contribute to its antiepileptic and
neuroprotective properties in epilepsy as well. In addition, melatonin has evidently been
shown to play a regulatory role in the cardiorespiratory system and sleep−wake cycles,
which may have positive implications toward epilepsy associated comorbidities, such as SUDEP. However, studies investigating the
changes in melatonin release due to epilepsy and melatonin’s antiepileptic role have been inconclusive and scarce, respectively. Thus,
this comprehensive review aims to summarize and elucidate the potential role of melatonin in the pathogenesis of epilepsy and its
comorbidities, in hopes to develop new diagnostic and therapeutic approaches that will improve the lives of epileptic patients,
particularly those who are drug resistant.
KEYWORDS: Oxidative stress, mitochondial dysfunction, nitric oxide, excitotoxic damage

■ INTRODUCTION
Epilepsy is a debilitating neurological disease that occurs as a
result of unprovoked, uncontrollable, and repetitive sudden
outburst of abnormal and excessive electrical discharges in the
neurons.1 Epilepsy affects 70 million people worldwide and
ranks third among all neurological disorders as a contributor
toward the global disease burden,2 especially given the
comorbidities associated with epilepsy such as cardiorespiratory
syndromes, neuropsychiatric problems, and cognitive deficits.
The prevalence rate of active epilepsy in just 2016 alone was 6.4
per 1000 persons, while the annual incidence rate of overall
epilepsy was 61.4 per 100 000 persons.3 However, approx-
imately 33% of patients with epilepsy were often resistant to
commonly prescribed antiepileptic drugs.4 This could be due to
the complex pathomechanism of epilepsy that is still not fully
understood, thus leading to the lack of therapeutic approaches or
intervention for epilepsy that is much needed to improve the
lives of these patients, especially for those who are drug resistant.
Neurotransmitter imbalance has been suggested to play the
most crucial role in the pathology of epilepsy,5 where an
imbalance of the excitatory and inhibitory neurotransmitters
may affect the functional and structural properties of the
receptors and ion channels they activate, causing neuronal
hyperexcitability and thus leading to repetitive and unprovoked
seizures.6 Neurotrasnmitter imbalance may cause or may be
initiated by several other neuronal pathologies as well such as
oxidative stress, nitrosative stress, mitochondrial dysfunction,
and neuroinflammation, which may further contribute to
epilepsy and its comorbidities.7−9 These pathologies were also
witnessed in other neurological disorders such as neuro-
degenerative diseases.8,10−14 The literature has shown that a
serotonin-derived hormone known as melatonin may exert
neuroprotective properties against neurological diseases by
targeting the aforementioned pathologies.15−20
Melatonin is a hormone synthesized at night by the
parenchymatous cells in the pineal gland in response to the
light information received through the retinohypothalamic
Received: February 10, 2021
Accepted: March 25, 2021
Published: April 5, 2021

© 2021 American Chemical Society https://doi.org/10.1021/acschemneuro.1c00083

1281 ACS Chem. Neurosci. 2021, 12, 1281−1292
ACS Chemical Neuroscience
pathways during the day.21,22 Melatonin receptors (MT1 and
MT2), which are expressed in the hippocampus, substantia
nigra, and ventral tegmental area, consist of seven trans-
membrane regions linked to the G protein.23 The intracellular
signal of these receptors is mediated by adenylate cyclase,
phospholipase C (PLC), guanylate cyclase, and activation of the
calcium and potassium channels.24 Thus, activation of these
receptors by melatonin regulates cellular ion flow25 and
therefore may be responsible for governing neuronal activity.
Melatonin may also interact with other specific membrane
nuclear receptors, such as calmodulin and tubulin-related
proteins to exhibit its antioxidant activity. Melatonin may act
as a free radical scavenger that may be stronger than vitamin E.26
It may also exert an antioxidative effect by increasing the levels of
other antioxidative enzymes, including superoxide dismutase,
glutathione peroxidase, and glutathione reductase. As circadian
rhythm disruption and increased oxidative stress may be some of
the important pathological causes of neurodegenerative/neuro-
logical diseases,16,27 melatonin which regulates them may serve
as a key therapeutic agent for these diseases.
Melatonin has shown preventive and therapeutic effects on
neurodegenerative diseases such as Alzheimer’s disease (AD),
Parkinson’s disease (PD), Huntington’s disease (HD), and
amyotrophic lateral sclerosis (ALS).15,18,20,28,29 It has been
observed that the risk of developing neurodegenerative diseases
increased with the decrease in melatonin levels in elderly
individuals.30 In addition, high doses of melatonin admin-
istration displayed very few side effects in patients with
neurodegenerative disorders, which strengthens the role of
melatonin as a neuroprotective agent.31,32 Melatonin may
provide its therapeutic effect on the pathology of neuro-
degenerative diseases by regulating the circadian rhythm,
oxidative stress, neuroinflammation, apoptosis, and mitochon-
drial dysfunction.15,18 Besides in neurodegenerative diseases,
these pathologies may also be present in epilepsy,19 and
therefore, researchers believe that the therapeutic properties of
melatonin may be transferable toward epilepsy as well. However,
currently, studies regarding the role of melatonin in the
pathology of epilepsy are still scarce and inconclusive.
Thus, this review aimed to elucidate the possible mechanism
of action of melatonin on epilepsy while comparing to the
neuroprotective properties in neurodegeneration. Melatonin’s
effects on epilepsy related neurotransmitters inbalance and its
comorbidities such as the effect on circadian rhythm and the
cardiac function were also taken into consideration. Therefore,
this review offers a comprehensive overview on the current
literature regarding melatonin on epilepsy while also providing
new insights into melatonin as a potential treatment strategy for
epilepsy, which in turn will improve the lives of epileptic patients
worldwide.
■
ROLE OF MELATONIN ON EPILEPSY
Reports on melatonin levels in epileptic patients have been
contradictory in the literature. Reiter and his colleagues (1995)
initially observed a normal circadian melatonin secretion pattern
in epilepsy and reported that nocturnal secretion of melatonin
was twice as high in untreated epileptic patients than treated
patients.32 Similarly, high melatonin levels have also been
observed after epileptic seizures in patients with persistent
epilepsy in a 1998 and in a 2007 study.33,34 However, low
melatonin levels were reported instead by patients with
intractable epilepsy in a 2000 study35 (Table 1). These
contradicting results suggest that there may be other factors
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besides circadian rhythm influencing the melatonin levels in
epilepsy patients which requires further investigation.
The study in 2000 may be supported by findings from current
studies showing that administration of melatonin improved
seizures, suggesting that high levels of melatonin may be
beneficial for epilepsy. When children with drug resistant
epilepsy were given 10 mg of melatonin daily due to their low
melatonin levels, the frequency of seizures decreased.36 Similar
results were supported by a case study involving a 1.5-month-old
girl with severe myoclonic epilepsy, who controlled her seizures
with melatonin treatment.37 Likewise, a study with six epileptic
children also showed that their seizures were controlled
effectively with oral melatonin treatment for 3 months.38
However, in contrast, a study by Coppolo and his colleagues
observed that 1 month melatonin treatment on children resulted
in 22.2% of them having had worsen seizures while only 5.5%
had good seizure control39 (Table 1). These conflicting results
suggest that melatonin may display both anticonvulsant and
proconvulsant properties in epileptic children. Further studies
may be warranted to determine the factor that governs this
switch between the two properties.
One possible factor may be the mechanism by which
melatonin exerts its effect on epilepsy. Melatonin modulates
the electrical activity of neurons by altering glutamatergic and
GABAergic neurotransmission functions.40 Besides that,
melatonin also suppresses neuronal activity by closing the
Ca2+ channel and limits the activity of NOS by reducing the
calcium entry into neurons.41 The latter limiting effect of
melatonin on NOS activity inhibits the formation of seizures by
preventing the formation of toxic NO, which in turn prevents
oxidative stress and mitochondrial damage as well. The
neuroprotective effect of melatonin against free radicals42 may
also prevent or improve memory impairments and hippocampal
neurogenesis induced by valproic acid,43 which are often found
in epileptic conditions.44,45
Another possible factor that may affect the duality in
melatonin property (anti/proconvulsant) is the melatonin
receptor interaction. The literature suggests that targeting the
MT1 or MT2 receptors may be effective for the development of
more effective therapeutic agents.46 The anticonvulsant effect of
melatonin has been related to the modulation of melatonergic
MT1/2 receptors.47 However, agomelatine, a melatonin
receptor agonist, has been reported to be ineffective against
electroshock and picrotoxin-induced seizures48 but appeared to
delay the development of seizures in PTZ (25 mg/kg, ip)
induced epilepsy in a mice model49 (Table 1). These data
suggest that the melatonin receptors may be the key factors
involved in melatonin anti/proconvulsant property, which could
also be governed by the duration of the receptor activation and/
or type of receptor (MT1 or MT2) being activated. However,
the evidence suggests that the activation of MT1 and MT2
melatonin receptors may provide a neuroprotective effect.50
Taken together, the literature suggests that melatonin may
have an important role in epilepsy, but its anti/proepileptic role
may be dependent on the mechanism of action (which will be
discussed further in this review) in the pathological pathways
and receptor activation, which unfortunately still requires
further investigation. Moreover, studies evaluating the level of
melatonin and its effects in different types of epilepsy may also
be needed to help better understand the role of melatonin in
epilepsy.
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 Table 1. Summary of Findings in Relation to Epilepsy Model Used, Type of Treatment, and Main Observations from Articles Selected for This Reviewa
type of study epilepsy model treatment schedule observations ref
1 Human study Patients with refractory temporal lobe Anticonvulsant therapy was continued. • Melatonin was decreased in epilepsy patients compared to controls at baseline 35
epilepsy and control group Benzodiazepines or barbiturates were not given. and increased 3-fold following seizures.
2 Human study 25 patients affected by epileptic seizures 3 mg oral synthetic fast-release melatonin • Melatonin affects seizure frequency poorly, but occasionally the seizure may 39
and mental retardation worsen or improve.
3 Human study 54 children with fever and epilepsy with Only melatonin was measured. • Supported the view that stimulation of melatonin production by convulsive 34
convulsive attacks crisis may contribute to the organism’s response to seizures.
4 Human study 100 patients diagnosed with idiopathic Patients receiving monotherapy were treated with one of the following • Significantly increased oxidative markers were observed in epilepsy patients 73
generalized epilepsy and a control antiepileptic drugs: compared to the control group.
group of 100 people • Carbamazepine • AEDs did not affect oxidative markers and suggested the presence of oxidative
ACS Chemical Neuroscience

• Phenytoin stress caused by the seizure.

• Valproate
• Clobazam
• Phenobarbital
• Lamotrigine
• Topiramate
• Levetiracetam
Patients who received polytherapy used more than one drug.
5 In vivo Valproic acid (VPA) (300 mg/kg) • VPA (300 mg/kg) • Rats receiving melatonin alone showed significant proliferation, survival, and 43
induced memory impairments in SD immature neuron diversity compared to control rats.
rats • Melatonin (8 (mg/kg)/day) • It shows that melatonin can prevent memory impairments and a reduction in
• VPA and melatonin treatment for 14 days hippocampal neurogenesis simultaneously induced by VPA.
6 In vivo Mouse model induced by • Melatonin (40 and 80 mg/kg) • Melatonin and agmatine lower the pentylenetetrazole-induced seizure 47

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pentylenetetrazole (PTZ) • Agmatine (10 and 20 mg/kg) threshold in mice via melatonin receptors (1/2).
7 In vivo 21 WAG/Rij male rats Experimental groups received normal saline (group I, 1 mL, intraperitoneally • The systemic administration of agomelatine and melatonin attenuated the 14
(ip)), agomelatine (group II, 40 mg/kg, ip), and melatonin (group III, 40 mg/ genetic absence epilepsy seizures in WAG/Rij rats.
kg, ip) injections for 7 days.
8 In vivo Animal model of PTZ (25 mg/kg, ip) • Agomelatine (10 mg/kg, po) • Agomelatine 10 mg/kg, po, effectively delayed development of kindling, 49
induced epilepsy in mice reduced seizure severity, and decreased % incidence.
• Luzindole (2.5 mg/kg, ip) • Luzindole reversed the protective effects of agomelatine while mCPP failed to
• mCPP (7 mg/kg, ip) for 5 weeks show such a reversal, indicating melatonergic (and not serotonergic)
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mechanisms in the observed effects.

9 In vivo 29 normal dogs and 33 dogs with Melatonin values were compared in dogs with epilepsy and healthy dogs. • There was no significant difference in daytime serum melatonin levels in 81
epileptic seizures were studied. normal dogs compared to dogs with seizures.
10 In vivo Mouse model induced by • Melatonin (40 and 80 mg/kg) • Melatonin exerts an anticonvulsant effect in the iv PTZ seizure paradigm, 77
pentylenetetrazole (PTZ) • L-arginine
(30, 60 mg/kg) which can be mediated by the NO/L-arginine pathway with expressed NOS.
• L-NAME (30 mg/kg)
11 In vivo 35 adult male NMRI mice induced with • Melatonin (40 and 80 mg/kg) • The administration of glibenclamide, the drug blocking the KATP channel, 80
pentylenetetrazole before PTZ injection reduced the anticonvulsant effect of melatonin.
• Glibenclamide (1, 3, and 10 mg/kg • Diazoxide and cromakalim as KATP channel openers increased the antiseizure
• Diazoxide (0.5, 1, and 5 mg/kg) effect of melatonin in the PTZ seizure model.
• Cromakalim (1, 10, and 30 mg/kg)
12 In vivo Rats with KA-induced status epilepticus • Melatonin (10 mg/kg for 14 days via sc osmotic minipumps) • Melatonin failed to suppress seizure incidence and intensity though the latency 82
and normotensive Wistar rats for seizure onset was significantly increased in SHRs.
• Melatonin attenuated the KA-induced increase in the level of lipid
peroxidation in the hippocampus in both SHRs and Wistar rats.
a
Abbreviations: AEDs, antiepileptic drugs; KA, kainic acid; mCPP, 1-(m-chlorophenyl)piperazine; NO, nitric oxide; NOS, nitric oxide synthase; PTZ, pentylenetetrazole; SHRs, spontaneously
Review

hypertensive rats; VPA, valproic acid.

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Figure 1. Possible mechanism of action of melatonin in the epilepsy pathology. Abbreviations are the following: AMPAR, α-amino-3-hydroxy-5-
methyl-4-isoxazolepropionic acid receptor; AQP4, aquaporin 4; Cyt c, cytochrome c; EAAT1/2, excitatoryamino acid transporter 1/2; GABAR, γ-
aminobutyric acid receptor; GLN, glutamine; GS, glutamine synthetase; HMGB1, high mobility group box 1; IL-1β, interleukin-1β; Kir4.1, inward-
rectifier potassium channel 4.1; mtPTPs, mitochondrial permeability transition pores; NMDAR, N-methyl-D-aspartate receptor; NOS, nitric oxide
synthase; RNS, reactive nitrogen species; ROS, reactive oxygen species; TNFα, tumor necrosis factor α; TRP, transient receptor potential; VGCC,
voltage-gated calcium channel.

■ ROLE OF MELATONIN ON THE PATHOLOGICAL

PATHWAYS OF EPILEPSY
Melatonin, Oxidative Stress, and Mitochondrial
Dysfunction. Age affects oxidative stress levels51 as well as
melatonin production levels. Melatonin production was found
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to be higher in younger individuals compared to older
individuals, as melatonin production decreases with age.52
Age-related decrease in melatonin levels has been associated
with dysfunctions in superchiasmatic nucleues (SCN), which
may lead to higher incidences of neurodegenerative disorders
such as AD, PD, HD, and ALS in the elderly population.53
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Endogenous synthesis of antioxidants decreases in parallel with
the decrease in production of melatonin in neurodegenerative
diseases such as AD, PD, HD, and ALS.54 Melatonin has proven
to be effective in preventing oxidative damage by preserving
mitochondrial homeostasis and has been protrayed as an
antioxidant in cultured neuronal cells and in animals treated
with various neurotoxic agents.55 Thus, this suggests that
melatonin may be an effective treatment toward age-related
neurological disorders such as neurodegenerative diseases due
to its antioxidant property.
Mitochondrial dysfunction has an important role in the
epileptogenesis process.48,56 Reduced activity of respiratory
complexes in mitochondria causes mitochondrial dysfunction
and therefore oxidative stress.57 This dysfunction may lead to
decreased adenosine triphosphate (ATP) production, disrup-
tion of proton potential, oxidative damage, and induction of
apoptosis. Synthesis of ATP may occur due to proton transitions
in the electron transport chain (ETC).58 As the electron flows, a
proton gradient takes place by pumping protons in the I, III, and
IV complexes. A decrease in the activity of one or more
respiratory chain complexes will result in an increase in electron
leakage and the formation of reactive oxygen species (ROS) and
reactive nitrogen species (RNS) accordingly.58 Most of the
oxygen (O2) consumed by the mitochondria will be reduced to
water in complex IV, but approximately 3−5% of the oxygen will
be converted into ROS in complex IV. ROS causes oxidative
damage, increases mitochondrial permeability transition pores
(mtPTPs), and stimulates apoptotic cascades with the release of
cytochrome c. Apoptosis may be prevented with the release of
antiapoptotic members of the Bcl-2 family.55,59,60 In vitro studies
have shown that melatonin increases Bcl-2 expression and
prevents apoptosis.61,62 Various animal models have also
witnessed this antiapoptotic property of melatonin,63−65 further
supporting its antioxidant property as well.
In addition, melatonin may increase the effectiveness of ETC
by limiting electron leakage and free radical formation.
Inhibition of electron leakage and free radical formation showed
that melatonin may protect the mitochondria from oxidative
damage.66,67 Melatonin also may prevent the opening of the
mitochondrial permeability transition pore (mtPTP) during
oxidative stress.68 It also may play a role in protecting the
mitochondria from oxidative damage by preventing the
oxidation of cardiolipin.69 Cardiolipin, a phospholipid found
at the level of the inner mitochondrial membrane, is required for
several mitochondrial bioenergetic processes and in mitochon-
drial dependent apoptosis stages.69 Additionally, melatonin has
also been known to increase the antioxidant potential of the cell
by stimulating the synthesis of antioxidant enzymes including
superoxide dismutase, glutathione peroxidase, and glutathione
reductase, thereby increasing glutathione levels.55 Since
oxidative stress and mitochondrial dysfunction have been
suggested as a contributing factor for the onset and evolution
of epilepsy,14,64 this evidence suggests that melatonin may exert
its neuroprotective and antiepileptic properties by being both an
antioxidant and an antiapoptotic in the pathway of mitochon-
drial dysfunction.
Melatonin may also exert its neuroprotective role by reducing
the formation of nitric oxide (NO) in the mitochondria70
(Figure 1). NO is a gaseous compound that may easily enter the
mitochondria through its membranes. NO strongly interferes
with components of the respiratory chain in the mitochondria,
particularly with the cytochrome c oxidase.71 Increasing
amounts of O2 may interact with NO to form the highly toxic,
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peroxynitrite anion (ONOO−). ONOO− may further interfer
with respiratory chain complexes (mostly I and IV complexes)
and trigger free radical-mediated chain reactions.71 This
situation may cause the induction of the mtPTP and activation
of the apoptotic pathways.
Oxidative stress caused by NO may lead to neuronal apoptosis
and the initiation and progression of epilepsy.72 Studies have
shown that NO synthesis was found to be increased in acute and
chronic epilepsy.73,74 In addition, NO may also play a role in the
development of neuroinflammation in epilepsy through the
mitogen-activated protein kinase (MAPK) and the
phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)
signaling pathways.75 Studies have also confirmed that
mitochondrial nitric oxide synthase (mtNOS) was responsible
for mitochondrial dysfunction observed during sepsis, but
melatonin has the ability to protect against this.76 Thus,
melatonin may present its antiepileptic property through the
NO pathway of the mitochondria. In an epilepsy model induced
by pentylenetetrazole (PTZ), intraperitoneal melatonin admin-
istration (40 and 80 mg/kg) was found to significantly increase
the seizure threshold of the animals through the NO/L-arginine
pathway.77 In further support, studies have also suggested that
melatonin may enhance the antiseizure effects of morphine
through the NO pathway.78,79
A study conducted in 2020 showed that the anticonvulsant
effect of melatonin may also be achieved by increasing the
opening of the potassium (KATP) channels80 (Table 1).
Potassium channels such as Kir6.1 and Kir6.2 channels have
been shown to be involved in the oxidative stress and
mitochondrial dysfunction of epilepsy, and thus its relationship
with melatonin should be investigated further.
Taken together, oxidative stress and mitochondrial dysfunc-
tion which increases with age may result in neuronal damage
(NO, ROS) and death (apoptosis) leading to a shear load of
neurological disorders, especially neurodegenerative diseases
and epilepsy. Melatonin may act as an effective antioxidant and
an antiapoptotic molecule, which may counteract or prevent the
oxidative stress and nitrosative stress, therefore suggesting it as a
possible therapy for neurological disorders, particularly epilepsy.
Melatonin and GABA/Glutamate Neurotransmitters.
In addition to oxidative stress and mitochondrial dysfunction,
glutamate excitotoxicity may also play an important role in
epilepsy.83 Glutamate is the main stimulating neurotransmitter
in the central nervous system. An increase in glutamate levels
may cause neuronal death in epileptic seizures.9 Glutamate may
cause cell death in two different pathways: excitotoxicity and
oxytosis. Glutamate-induced oxytosis is triggered by the
blockade of cystine/glutamate antiporter causing the gradual
depletion of glutathione, the major intracellular antioxidant.
When glutathione levels decreased below a certain threshold, an
increase in ROS and Ca2+ levels was observed, and apoptosis
may occur following this process. Glutamate excitotoxicity, on
the other hand, may be triggered by the overactivation of the
glutamate ionotropic receptors, resulting in an intense influx of
extracellular Ca2+. Glutamate excitotoxicity may also contribute
significantly to the production of reactive nitrogen species that
cause nitrosative stress.84
Intracellular calcium ion (Ca2+) overload may be caused by
glutamate excitotoxicity, which leads to the activation of the
neuronal cell death pathway85 and the epileptogenesis process.86
Mitochondrial dysfunction may cause Ca2+ influx from the
extracellular space through the cation channels. When the level
of calcium in the mitochondrial matrix increased significantly, a
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nonspecific increase in the permeability of the inner
mitochondrial membrane may also occur.87,88 This is known
as the mitochondrial permeability transition (mtPT). Both Ca2+
and ROS are major mtPT regulators. Ca2+ overload may cause
mitochondrial-mediated apoptosis, leading to increased mtPT
pore opening, mitochondrial swelling, ATP hydrolysis, and loss
of respiratory control,85,89 therefore initiating neurodegenera-
tion and epileptogenesis pathway.
Besides that, during excitotoxicity, increased activation of
glutamate receptors via voltage gated calcium channel (VGCC)
and transient receptor potential (TRP) channels, in the epilepsy
pathogenesis, may be often accompanied by a decrease in the
level of GABA as well.88,90 Dysfunctions occurring in GABA
transmission have been associated with various types of epilepsy,
and mutations in the GABA genes may also cause epilepsy by
disrupting the GABA receptor excitability.91
Melatonin is believed to modulate the electrical activity of
neurons by decreasing the glutamatergic neurotransmission and
increasing the GABA-ergic neurotransmission.92 Melatonin may
positively modulate the activity of GABA receptors by increasing
GABA levels in the hippocampal and cerebral cortex, thereby
exhibiting an anticonvulsant effect.93 Furthermore, in chronic
epileptic hippocampus, glutamine synthetase may be disrupted,
which may increase the extracellular glutamate but may decrease
the GABA release, thus resulting in hyperactivity of neurons. It
has been previously reported that melatonin may prevent the
formation of seizures by enhancing the glutamate conversion
and reducing this glutamatergic neurotransmission.94 Melatonin
inhibits glutamatergic transmission through the inhibition of
nNOS and modulation of the oxidation−reduction (redox)
region of the N-methyl-D-aspartate (NMDA) receptors.17Addi-
Additionally, melatonin has also been reported to completely
inhibit glutamate-induced mitochondrial ROS production, Ca2+
influx increase, and neuronal cell death.83 These data strongly
indicate that melatonin may inhibit glutamate-induced
excitotoxicity and oxytosis through a direct antioxidant action
that specifically targets the mitochondria.
Moreover, studies have shown that melatonin may also
mediate Ca2+ regulation in epilepsy.95 At the cellular level, Ca2+
influx occurs through the VGCC, TRP, and NMDA-dependent
calcium channels which initiate/regulate seizure activities.95
Excessive increase of intracellular Ca2+ concentration in epilepsy
induces ROS production, apoptosis, caspase activations, neuro-
nal hyperexcitability, and neuronal cell death. Melatonin
administration in epilepsy has been shown to exhibit a decrease
in neuronal cell death and seizure activity by decreasing the
intracellular Ca2+ concentration through the inhibition of the
VGCCs, TRP channels, and NMDA receptors.96,97 Melatonin
may inhibit NMDA-induced neuronal stimulation by inhibiting
NO synthase (nNOS).98
Thus, the evidence showed that an increase in glutamatergic
neurotransmission and a decrease in GABA-ergic neuro-
transmission may play an important role in the progression
and onset of epilepsy. As melatonin has an effect on reducing
glutamatergic neurotransmission and increasing GABA-ergic
neurotransmission, this suggests that melatonin therapy may be
effective in regulating these two neurotransmitter functions in
hopes of treating/controlling epileptic conditions efficiently.
Melatonin and Neuroinflammation. In addition to
glutamate excitoxicity and oxidative stress, neuroinflammation
may also play an important role in the epilepsy pathogenesis.12
Studies have shown the involvement of glial cells known as
astrocytes in epilepsy. It was observed that the Kir4.1 channels,
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which are specifically expressed in brain astrocytes, were
downregulated in an experimental model of epilepsy.99 This
inhibition of the Kir4.1 channels contributed to the formation of
epileptic seizures due to the increased levels of [K+]o and [Glu]o
at the astrocytic synapses.99 Decreased expression of astrocytic
glutamate transporters (EAAT1, EAAT2) has also been
observed in the astrocytic membranes of human epileptic
hippocampus.100 The altered activity of astrocytic glutamate
transporters may cause an increase in glutamate concentration
and consequently glutamate excitotoxicity, thus leading to a
lower seizure threshold, recurrent seizures, and neuronal death.9
Pharmacological inhibition of glial glutamate transporters may
cause the neuronal NMDA receptors to open and the synaptic
currents to be prolonged, thus reducing the threshold for
epileptiform activation.101
Besides Kir4.1 channels, aquaporin-4 (AQP4) channels may
also mediate glutamate uptake in astrocytes by contributing to
the K+ buffering, as Kir4.1, and AQP4 channels may be localized
together in the astrocytic membrane.102,103 Considering that
both the Kir4.1 and AQP4 channels facilitate the uptake of
glutamate and water molecules into the astrocytes by binding to
excitatory amino acid transporters (EAATs), it is important to
investigate the interactive role between Kir4.1 and AQP4
channels in the astrocytes, especially in the context of epilepsy.
Only then may investigations regarding the effect of melatonin
on astrocytes, in terms of Kir4.1, aquaporin 4 (AQP4), and
glutamate, be effectively explored, in terms of elucidating the
pathological mechanism of epilepsy.
As for neuroinflammatory cytokines, interleukin (IL) 1β has
been shown to increase the extracellular glutamate levels by
increasing the NMDA-mediated glutamate release from synaptic
terminals of high mobility group box 1 (HMGB1) and tumor
necrosis factor (TNF) α.104 Additionally, one study noted that
changes in Kir4.1 expression that occurred in epilepsy-
associated lesions were likely to be affected by the local
inflammatory environment, particularly by the inflammatory
cytokine IL-1.105 Similarly, TNF-α may induce glutamate
release from both microglia and astrocytes, leading to glutamate
excitotoxicity which may increase neuronal excitability and may
contribute to epileptic activity. As with glutamate excitotoxicity,
neuroinflammation may also contribute to mitochondrial
dysfunction.106−108 TNF-α may mediate mitochondrial dys-
function and neuronal death via the TNF-R1 receptor.109 TNF-
α may also induce neuronal channelopathies such as epilepsy,
through its effects on the AMPA receptors as well as GABAA
receptors.110 TNF-α may enhance neuronal excitability by
promoting the induction of neuronal NMDA-NR1 receptors
and endocytosis of GABAA receptors.110 On the other hand, IL-
1β may cause neuronal damage by initiating excitotoxicity and
increasing inducible NOS (iNOS) production via the IL-R1
signaling. In addition, TNF-α and IL-1β may mediate the
activation of protein kinases such as PI3K and PKC, which may
play a role in epilepsy and may be involved in neuro-
inflammation as well as in functional modifications of neuronal
receptors and voltage-gated ion channels.111
The release of proinflammatory cytokines such as TNF-α and
IL-1β may be suppressed by melatonin112 (Figure 1), suggesting
melatonin as an anti-inflammatory therapy for epilepsy.
Melatonin may modulate both the proinflammatory and anti-
inflammatory cytokines in the neuroinflammatory pathway.113
The literature has also shown that melatonin may prevent the
overactivation of glia cells.114 When rats were treated with
melatonin, a significant reduction in hippocampal microglia
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calcium content, microglia activation, and the production of
inflammatory factors were observed.114 Therefore, these suggest
that melatonin may also play a strong role in the neuro-
inflammatory pathway of epilepsy.
■
ROLE OF MELATONIN ON EPILEPSY ASSOCIATED
COMORBIDITIES
Besides its effect on the pathology of epilepsy, melatonin also has
been suggested to have an effect on epilepsy related
comorbidities such as neuropsychiatric disorders, arthritis,
dementia, cardiorespiratory dysfunction, and sleep disorders.
However, this review will only focus on the effects of melatonin
on the cardiac system and circadian rhythm, as its effects on
other comorbidities could be explained through the similar
pathologies as mentioned previously, such as neuroinflamma-
tion, neurotransmitter imbalance, and oxidative stress.
Cardiac System. One of the most devastating comorbidities
of epilepsy is the dysfunction in the cardiorespiratory system
leading to SUDEP. Sudden unexpected death in epilepsy
(SUDEP) is the leading cause of death in epilepsy patients.
Although the exact initiation factor of SUDEP may still be
unknown, disturbances in cardiac functions such as tachycardia,
bradycardia and asystole and autonomic functions may cause
SUDEP.115 In epilepsy, an imbalance may occur between the
sympathetic and parasympathetic systems due to the increased
sympathetic activity, which may cause deterioration in heart
functions, thereby leading to SUDEP.115 Currently, in order to
prevent cardiac dysfunction in epilepsy, the vagus nerve, which is
a parasympathetic nerve, may be stimulated.116 Stimulation of
the vagus nerve may help to balance the increased sympathetic
activity and reduce the increased heart rate in epilepsy.
Melatonin may exhibit a neuroprotective effect in ischemia/
reperfusion (I/R) injury.117 ROS produced at the complexes I
and III of the respiratory chain may be responsible for the injury
seen in the cardiac I/R state. Literature evidence suggested that
the opening of the mtPT pore was responsible for
cardiomyocyte death during I/R.118,119 In the case of
reperfusion, Ca2+ flow to the mitochondria and the resulting
explosion of ROS production may cause the mtPT channels to
open. This may lead to mitochondrial depolarization, swelling,
and rupture of the outer mitochondrial membrane resulting in
the outflow of cytochrome c and other proapoptotic factors,
which may lead to cell death through apoptosis or necrosis.120
The protective effect of melatonin during the I/R sequence has
been attributed to its effect in inhibiting mtPT pores and
preserving the content and integrity of the cardiolipin
molecules.117 Increased peroxidized cardiolipin levels together
with increased Ca2+ overload may contribute to mtPT pore
opening during reperfusion. Thus, melatonin may prevent
cardiac malfunction by protecting against the oxidative damage
of cardiolipin and by preventing the opening of the mtPT
channel.
In addition, melatonin treatment may cause significant
reductions in infarct size.64,121 In a rodent epilepsy study
utilizing an acute myocardial infarction (AMI) model, it was
observed that the epileptic rats had significant changes in the
electrocardiogram intervals compared to control rats during the
stabilization, ischemia, and reperfusion periods. It was also noted
that epileptic rats showed a significant increase in the QRS
interval during the stabilization period, as well as a decrease in
the P wave and QT interval (P < 0.05 for both) compared to
control rats. These results suggest that electrical conductivity
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may change in the heart tissue during an AMI episode, which is
dependent on seizure activity.
Changes in the electrocardiogram in epilepsy may also be
associated with SUDEP.122 Interestingly, in a study in which
arterial blood pressure, heart rate, forearm blood flow, and
thoracic impedance were measured to determine the effect of
melatonin on sympathetic nerve activity and arterial blood
pressure in humans, melatonin managed to attenuate the
sympathetic increases and mediate the changes in the
baroreflexes.123 Considering that melatonin may be effective
in protecting cardiovascular damage and inhibiting sympathetic
activity,124 the possible mechanism of action of melatonin on
heart functions and SUDEP in epilepsy should be explored
further, as this may improve and protect the lives of epileptic
patients. Studies on melatonin receptors in epilepsy may
contribute to the development of new and more accessible
treatment strategies for epilepsy besides vagus nerve stimulation.
Circadian Rhythm. Melatonin is primarily a hormone that
controls human sleep−wake cycles. The literature has indicated
the existence of bidirectional interactions between sleep,
circadian rhythm, and epilepsy,125 suggesting melatonin’s role
in sleep and circadian rhythm may be worth exploring for
epilepsy treatment.
Seizures may negatively affect sleep patterns, which in turn
facilitates seizure formation.126 In a study on core clock genes
that contribute to epileptic sensitivity and regulate circadian
rhythms, expression of the core clock genes PER1 and CRY1 was
found to be irregular during epileptogenesis in a poststatus
epilepticus animal model of mesial temporal lobe epilepsy.127
However, BMAL1, CLOCK, and CRY2 expression was found to
decrease gradually during epileptogenesis instead.127 Core clock
genes may cause seizure periodicity by rhythmically disrupting
the neuronal inhibitor and stimulus balance.128 In a study
utilizing epileptic brain samples obtained from focal cortical
dysplasia (FCD) and tuberous sclerosis complex (TSC) cases, it
was observed that the expression of the CLOCK gene was
decreased in the epileptogenic tissue compared to the control
tissue.129 Additionally, the same study also utilized the Emx-Cre
Clockflox/flox mouse model that showed that these mice
exhibited sleep-related seizures due to the conditional deletion
of the CLOCK gene in the excitatory neurons.129 These results
showed that the dysfunction of the core clock genes may play an
important role in the development of epilepsy and that sleep
disorders may be associated with epilepsy.
Interictal epileptiform discharges may lateralize in the
epileptogenic hemisphere during NREM and REM sleep.130
In a meta-analysis study using conventional and intracranial
EEG, the rate of formation of focal epileptiform discharges was
1.11 times higher in the waking state, 1.75 times higher in the
first stage of NREM, 1.69 times higher in the second stage of
NREM sleep, and 2.46 times higher in the third stage of NREM
sleep.131 These data suggested that epileptiform discharges were
highly activated in the third phase of NREM sleep. On the
contrary, the REM stage of sleep may suppress the epileptiform
discharges. There may be increasing evidence that suggests the
distribution of epileptiform discharges may not be homoge-
neous during both NREM sleep and REM sleep. During NREM
sleep, centrotemporal discharges not only may increase in
amplitude but may become more frequent as well,130 but this
may not be seen in REM sleep.
The neuroprotective properties of melatonin as well as its
regulatory effects on circadian disorders have shown that
melatonin can be effective as a therapeutic agent in the
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symptomatic treatment of neurological diseases.55 Melatonin
has the capacity to alter the timing of mammalian circadian
rhythms by functioning in harmony with light to synchronize the
light−dark cycles that dominate the circadian rhythms. Plasma
melatonin was found in high levels during the night and low
levels during the day.23 Melatonin may reach its highest plasma
concentrations between 02:00 and 04:00 h. Longer nights were
associated with longer duration of melatonin secretion.23 Thus,
melatonin may often be defined as a dark signal.126
In mammals, melatonin may be critical in regulating seasonal
changes for physiological, neuroendocrine, and reproductive
functions. These actions of melatonin may be processed in the
nuclei of the hypothalamus and the pars tuberalis (PT) of the
pituitary. Changes in melatonin receptor expression and
endogenous melatonin production have been associated with
circadian rhythm sleep disorders as well as neurodegenerative
diseases such as AD and PD.23,132 Considering this role of
melatonin in neurodegenerative diseases, it may be speculated
that this effect may also play a role in epilepsy due to its
relationship with sleep and circadian rhythm as well.
■
CONCLUSION
Epilepsy is one of the most highly prevalent conditions among
neurological disorders. Despite the rapid progression in epilepsy
research, the complex pathomechanism of epilepsy may not be
fully understood yet, therefore attributing to the lack of
therapeutic approaches in epilepsy, especially for drug-resistant
epilepsy patients. However, pathologies such as apoptosis,
mitochondrial dysfunction, oxidative stress, ion channel and
receptor modifications (genetic or functional), neurotransmitter
imbalance, and neuroinflammation, which all have been
witnessed in neurodegenerative diseases may explain the
pathology in epilepsy as well due to their similarities. These
pathologies of epileptogenesis may also play a role in its
comordities such as SUDEP. Since sleep affects epilepsy and
melatonin is a neurotransmitter that is governed by sleep
(circadian rhythm), researchers believed that melatonin too may
play a role in epilepsy. However, thus far, studies on the role of
melatonin on epilepsy may be inconsistent, suggesting a
proconvulsant, an anticonvulsant, or no effect displayed
(Table 1).
These contradictory results found in experimental studies
may be due to the different types of epilepsy and seizure models
studied as well as the differences in age of participants among
population studies. Considering the therapeutic effects of
melatonin on apoptosis, mitochondrial dysfunction, nitric
oxide, oxidative stress, and neuroinflammation as well as the
neuroprotective effects of melatonin on neurodegenerative
diseases, melatonin may be a potential candidate for effective
epilepsy treatment, especially for those who are drug resistant.
However, future studies should take into account the age,
epilepsy, or seizure type, as well as the time of the seizure and
sleep patterns before melatonin therapy may be recommended
for epileptic patients to improve their quality of lives.
■
AUTHOR INFORMATION
Corresponding Author
Mohd. Farooq Shaikh − Neuropharmacology Research
Laboratory, Jeffrey Cheah School of Medicine and Health
Sciences, Monash University Malaysia, 47500 Selangor,
Malaysia; orcid.org/0000-0001-9865-6224;
Email: farooq.shaikh@monash.edu
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Authors
Enes Akyuz − University of Health Sciences, International
Medicine Faculty, Department of Biophysics, Istanbul, Turkey
Irem Kullu − Medical School, Yozgat Bozok University, 66100
Yozgat, Turkey
Alina Arulsamy − Neuropharmacology Research Laboratory,
Jeffrey Cheah School of Medicine and Health Sciences, Monash
University Malaysia, 47500 Selangor, Malaysia; orcid.org/
0000-0003-0993-5622
Complete contact information is available at:
https://pubs.acs.org/10.1021/acschemneuro.1c00083
Author Contributions
E.A. and I.K. conceived, carried out the literature review, and
drafted the manuscript. E.A., A.A., and M.F.S. provided critical
inputs and revised and edited the final version of the manuscript.
All authors have read and approved the final manuscript.
Funding
This work does not receive any sort of financial assistance from
any funding agency.
Notes
The authors declare no competing financial interest.
Ethics Statement: An ethics approval was not required for this
study as it utilized available data from published research
articles.
■
ACKNOWLEDGMENTS
This study acknowledges strong support from the Yozgat Bozok
University Medical Faculty.
■
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